Glioblastoma multiforme (GBM) is the most malignant form of brain cancer and remains one of the most aggressive forms of all human cancers with a median survival of just over one year despite multi modality therapy. GBM has been shown to contain cancer stem cells that are drive tumor growth. This finding has led to paradigm shift in developing effective therapies by exploiting tumor stem cell properties and vulnerabilities. A clear understanding of early epigenetic events that contribute to cancer stem cell differentiation and proliferation will be essential to develop pharmacologic strategies to target them. In this proposal, we aim to elucidate genomic regions that are susceptible for epigenetic aberrations in brain tumor stem cells using high throughput tag sequencing. This data will be used to learn how these aberrations lead to deregulation of gene expression and other genomic elements that orchestrate glioblastoma tumorigenesis and pathogenesis. These studies will have a two fold potential impact: a) provide new insights into mechanisms that contribute to gliomagenesis and b) provide sensitive and robust targets for development of rational therapeutic intervention of glioblastoma. PUBLIC HEALTH RELEVANCE: Patients with glioblastoma multiforme face a deadly disease with limited treatment options. Identification of genomic regions susceptible to epigenetic aberrations in brain tumor stem cells holds a great promise for developing effective therapies for aggressive and recurrent glioblastoma. The changes in promoter methylation patterns and the expression level of key genes may have diagnostic, therapeutic or prognostic significance for the successful development of effective treatment.